4.2 Review

Chronic lymphocytic leukemia: a clinical and molecular heterogenous disease

Journal

CANCER GENETICS
Volume 206, Issue 3, Pages 49-62

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.cancergen.2013.01.003

Keywords

Chronic lymphocytic leukemia; FISH; cytogenetic aberrations; next-generation sequencing

Funding

  1. Spanish Fondo de Investigaciones Sanitarias [02/1041, FIS 09/01543, PI12/00281]
  2. Caja de Burgos-Banca Civica, Proyectos de Investigacion del SACYL [106/A/06]
  3. Accion Transversal del Cancer project
  4. Instituto de Salud Carlos III (ISCIII)
  5. Spanish Ministry of Science and Innovation
  6. Cancer Research Foundation of Salamanca University
  7. Redes de Investigacion RTIIC (FIS)
  8. Ayuda Predoctoral FIS de Formacion en Investigacion by the Spanish Fondo de Investigaciones Sanitarias

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The clinical heterogeneity that characterizes chronic lymphocytic leukemia (CLL), with survival times ranging from months to decades, reflects its biological diversity. Our understanding of the biology of CLL has helped us identify several markers of prognostic significance, by which CLL can be differentiated into several distinct diseases. The presence of specific chromosomal abnormalities is a prognostic indicator of disease progression and survival. Conventional cytogenetic analyses have revealed chromosomal aberrations in 40-50% of patients, but the detection of abnormalities is limited by the low mitotic activity of CLL cells. Metaphase analysis has recently undergone a revival because the metaphase yield has been improved by stimulation of CLL cells with alternative methods. Fluorescence in situ hybridization identifies chromosomal changes in approximately 80% of patients with CLL, and comparative genomic hybridization using high-density arrays (i.e., array comparative genomic hybridization [aCGH]) enables high-resolution genome-wide scanning for detecting copy number alterations in a single hybridization. The mutational status of the immunoglobulin heavy chain variable (IGHV) genes identifies two subsets of CLL with different outcomes. Unfortunately, the determination of IGHV mutation status may not be practical in all laboratories, and for this reason characteristics that are correlated with IGHV mutation status are needed-zeta-chain associated (TCR) protein kinase 70 kDa (ZAP-70) being that most commonly used currently in routine clinical practice. Whole genome sequencing has offered new insights into the mutational status of the disease, highlighting the role of several genes previously unrelated to CLL. Of these, NOTCH1 and SF381 are the most frequently mutated genes that predict poor prognosis. MicroRNA alterations are also involved in the initiation and progression of CLL, and the expression levels of some microRNAs correlate with previously established prognostic markers such as IGHV mutation status or ZAP-70. In addition, both global and gene-specific aberrant DNA methylation have been observed in CLL. Aberrant methylation has been described for genes that are specifically deregulated in CLL, such as BCL2, TCL1, and ZAP-70. Expanding knowledge of aberrant methylation profiles in CLL has a potential future impact on diagnosis, prognosis, and prediction of treatment response in CLL patients.

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